Pharmacokinetic/Pharmacodynamic Modelling of the Eosinopenic and Hypokalemic Effects of Formoterol and Theophylline Combination in Healthy Men

Abstract Interactions of formoterol and theophylline were evaluated with the use of pharmacokinetic-pharmacodynamic (PK/PD) modelling. Oral doses of 144 μg of formoterol and 375 mg of theophylline were given separately or combined to healthy subjects. As effect parameters, plasma eosinophil and potassium concentrations were used. Kinetic interactions between formoterol and theophylline were not found. Plasma drug concentrations were linked to the observed effects via an effect compartment model with a sigmoid E max model. The E max values±SD for the hypokalemic effects were 2.29±0.78 mmol/l for formoterol and 1.64±1.16 mmol/l for theophylline ( P >0.05). The E max values for the eosinopenic effects were fixed at zero. The EC 50 values of the eosinopenic and hypokalemic effects were respectively 91.4±38.2 pg/ml and 128.4±52.9 pg/ml for formoterol, and 11.9±4.6 μg/ml and 15.5±4.8 μg/ml for theophylline. Effects of both drugs combined were described with a non-competitive interaction model. The correlation coefficients of the fits of the eosinopenic and hypokalemic effects were respectively 0.9520±0.0311 and 0.9371±0.0227, supporting our hypothesis of non-competitive interaction.